Abstract

ED01-01

Our improved understanding of the molecular basis of malignancy has led to the identification of many new biochemical targets for therapy. While some of the drugs developed to affect specific targets have demonstrated activity in clinical trials and have subsequently gained FDA approval, many questions remain about the optimal way to translate basic research observations into clinical practice. These questions include preclinical identification of therapeutically relevant targets with high fidelity and demonstration of clinical benefit in well-designed controlled clinical trials. There are even more vexing concerns as to whether incorporation of biomarkers or imaging studies into our current clinical trial designs will optimize the development of targeted agents and whether a subset of such biomarkers can be validated as surrogate markers for clinical benefit. Such optimization could lead to an increase in the percentage of novel agents entering phase I trials that ultimately gain FDA approval or increasing the speed with which novel agents move through the various phases of drug development. Previous publications (1, 2) suggest that measurement of drug effects in tumor or surrogate tissue or use of functional imaging studies have not improved the efficiency of phase I clinical trials and did not contribute to the selection of a dose for phase II study. Likewise, limited data from phase II efficacy studies of targeted agents typically employed a standard primary endpoint such as objective response with only a limited number of studies qualifying patients for therapy through measurement of target expression or use of enrichment designs. No phase II studies used measurement of a surrogate endpoint to assess anticancer drug effects with, or in place of, clinical endpoints (3). Despite the practical challenges highlighted by these data, effectively incorporating translational endpoints into early clinical trials of novel targeted agents remains appealing and suggests that clinical trials with translational endpoints require more extensive planning to demonstrate their relevance. We will consider how appropriate planning can begin to address the challenges inherent in designing successful translational clinical trials that contribute essential information to drug development and ultimately facilitate the approval of targeted anticancer agents.References